Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely, Ru-sq ([Ru(DIP)2(sq)](PF6) (DIP: 4,7-diphenyl-1,10phenanthroline, sq: semiquinonate ligand), we describe in this work a structure-activity relationship (SAR) that involves a broader range of derivatives resulting from the coordination of different catecholate-type dioxo ligands to the same Ru(DIP)2 core. More in detail, we chose catechols carrying either electron-donating or electronwithdrawing groups EDG or EWG and investigated the physico-chemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep red positively charged complexes 1-4 in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes 5 and 6, on the other hand, are blue/violet neutral complexes, which carry an EWG substituted dinegatively charged catecholate ligand. The biological investigation of complexes 1-6 led to the conclusion that the difference in their physico-chemical properties has a strong impact on their biological activity. Thus, complexes 1-4 expressed much higher cytotoxicities than complexes 5 and 6. Complex 1 constitutes the most promising compound of the series and was selected for a more in-depth biological investigation. Apart from its remarkably high cytotoxicity (IC50 = 0.07-0.7 µM in different cancerous cell lines) complex 1 was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e. nucleus, lysosomes, mitochondria and cytoplasm) is extremely advantageous in the search of a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex 1 with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its 4 outstanding cytotoxicity, make complex 1 a valuable candidate in the field of chemotherapy research. Noteworthy, a preliminary biodistribution study on healthy mice demonstrated the suitability of complex 1 for further in vivo studies.

<div>Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely Ru-sq ([Ru(DIP)2(sq)](PF6) (DIP: 4,7-diphenyl-1,10-phenanthroline, sq: semiquinonate ligand), we describe in this work a structure-activity relationship (SAR) that involves a broader range of derivatives resulting from the coordination of different catecholate-like dioxoligands to the same Ru(DIP)2 core. More in detail, we chose catechols carrying either electron-donating or electronwithdrawing groups EDG or EWG and investigated the physico-chemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep red positively charged complexes 1–4 in which the preferred oxidation state of the dioxoligand is the uninegatively charged semiquinonate. Complexes 5 and 6, on the other hand, are blue/violet neutral complexes which carry an EWG substituted dinegatively charged catecholate ligand. The biological investigation of complexes 1–6 led to the conclusion that the difference in their physico-chemical properties has a strong impact on their biological activity. Thus, complexes 1–4 expressed much higher cytotoxicities than complexes 5 and 6. Complex 1 constitutes the most promising compound of the series and was selected for a more in-depth biological investigation. Apart from its remarkably high cytotoxicity (IC50 = 0.07–0.7 μM in different cancerous cell lines) complex 1 was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e. nucleus, lysosomes, mitochondria and cytoplasm) is extremely advantageous in the search of a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex 1 with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its outstanding cytotoxicity, make complex 1 a valuable candidate in the field of chemotherapy research.</div>

After the first successful clinical trials of monometallic photosensitizers (PSs) for photodynamic therapy (PDT), the use of polynuclear complexes is currently coming to the fore. These increasingly complex systems bear a high potential to overcome the drawbacks of their mononucleic peers by, for example, increasing the solubility of the PDT PSs and therefore their pharmacokinetic behavior, changing their internal quantum, and singlet oxygen efficiencies or adding supplementary imaging or therapeutical modalities, thus opening up the field for approaches in personalized medicine by combining therapy and diagnosis together in a single treatment. In this review, the most promising examples of polymetallic complexes used as PSs for anticancer PDT are presented.